Human immunodeficiency virus (HIV) is etiologically associated with the acquired immunodeficiency syndrome (AIDS). Promising new approaches being developed to control HIV infection and AIDS include gene therapy using retroviral vectors to deliver a protective gene(s) or information. One objective of this project is to develop HIV-, particularly HIV-2-, based retroviral vectors. HIV has the obvious advantage of cell tropism and HIV-2 has the added advantage of being able to infect stem cells. A series of HIV-2-based delivery vectors have been constructed, containing long terminal repeats (LTR) for regulated expression, baa sequences for packaging efficiency and the neo genes for cell selection. A second generation vector containing accessory genes and env gene or parts thereof have also been constructed. These vectors are being used to precisely define the genetic information necessary for efficient packaging of heterologous ribonucleic acid (RNA) encased within the subgenomic HIV-2 RNA. This is being done both by obtaining human T-cell lines stably transfected with these vectors followed by HIV-2 challenge and by introducing these vectors into HIV-2 encoding packaging cell lines. One such cell line containing HIV-2 gag-pol in one vector and env in a second vector, both driven by Rous sarcoma virus promoter (LTR), has been obtained. This cell line seems to provide all the gene products needed for packaging of HIV-2 encased heterologous RNA. During previous studies in the mapping of HIV-2 Tat functional domains, it was discovered that HIV-2 provirus downmodulated HIV-1 expression. Further studies have confirmed receptor-independent HIV-2 mediated intracellular inhibition of HIV-1. This inhibition apparently involves transcriptional downmodulation of HIV-1 expression. The HIV-2 gene(s) responsible for the phenomenon are being mapped. These studies, combined with the development of the HIV-2 vectors, could provide PERIOD